Fibre-Free Transdermal Therapeutic System and Method for its Production

ABSTRACT

The present invention is directed to transdermal therapeutic systems that are free of fibrous constituents, as well methods for producing such transdermal therapeutic systems. A preparation containing active substance is applied by a printing method onto the pressure-sensitive adhesive layer of the transdermal therapeutic system. Exemplary printing methods include application methods based upon a distributor plate of an application device.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional U.S. patent application Ser. No.11/885,716, filed Apr. 11, 2008, pending, which is a National StageApplication of International Application No. PCT/EP2006/001840, filed onFeb. 28, 2006, which claims priority of German application number 102005 010 255.7, filed on Mar. 7, 2005. Each of U.S. patent applicationSer. No. 11/885,716, filed Apr. 11, 2008; International Application No.PCT/EP2006/001840; and German application number 10 2005 010 255.7 arehereby incorporated herein in their entirety.

FIELD OF THE INVENTION

The present invention relates to transdermal therapeutic systems (TTSs)and to methods for their production. More particularly, the inventionrelates to transdermal therapeutic systems which do not contain anyfibrous constituents.

The invention further relates to methods for the production oftransdermal therapeutic systems wherein the systems are produced withoutthe use of fibrous constituents and are loaded with an active substanceby a printing method.

BACKGROUND OF THE INVENTION

Transdermal therapeutic systems are systems for the controlledadministration of pharmaceutical active substances via the skin. Theyhave been used for some time for treating various diseases, physical aswell as mental dysfunctions, complaints and indispositions. Transdermaltherapeutic systems are layered products in the form of patchescomprising an active substance-impermeable backing layer, at least oneactive substance-containing reservoir layer or matrix layer, possibly amembrane controlling the rate of active substance release, and adetachable protective layer, which is peeled off the TTS before thelatter is used.

To fix a transdermal therapeutic system to the skin and to ensure acontrolled administration of the active substance, the TTS is providedwith a pressure-sensitive adhesive layer. This pressure-sensitiveadhesive layer may be identical to the active substance-containingmatrix layer or to the skin-facing active substance-containing layer,but may also be provided in addition thereto if the (skin-facing) activesubstance-containing layer or the, optionally provided, membrane is notpressure-sensitive adhesive.

Commonly used transdermal therapeutic systems are those which have anactive substance-containing reservoir made up of a nonwoven fabric or apaper, that is, of a fibrous material. The nicotine-containing TTSNICOTINELL® may be mentioned as an example for such transdermaltherapeutic systems. Such nonwoven-comprising TTSs can be produced, forexample, in accordance with the method described in EP 0 261 402 A1.

The backing layer of a TTS must be impermeable to the active substancecontained in the TTS in order to prevent undesirable exiting of theactive substance from the side of the TTS which is averted from theskin. Materials used for this purpose are, in particular, metal foils,special plastic films as well as composite laminates of these materials.The most frequently used materials are composite laminates of aluminum,and plastic materials such as polyethylene terephthalate. The advantageof these composite laminates is that aluminum foils can be produced atlow cost and are impermeable to almost all pharmaceutical activesubstances. In addition, aluminum foils are impermeable to light, whichaffords a reliable protection against light, particularly forlight-sensitive active substances.

A disadvantage of transdermal therapeutic systems that are provided witha backing layer which comprises an aluminum foil and/or colored plasticfilms consists in that they invariably are visually conspicuous on theuser's skin. Even if the TTS adhering to the user's skin can be coveredby wearing clothes, there is a danger that a TTS having such a backinglayer will meet with very little acceptance on the part of the user.

For this reason, TTSs have become recently available which comprise atransparent backing layer and wherein the other layers, too, arepermeable to light. In use, these TTSs are almost invisible against theskin to which they adhere since the user's natural skin color is visiblethrough the TTS.

A method for the production of transdermal therapeutic systems having atransparent backing layer is described in U.S. Pat. No. 5,626,866. Inthis method, an active substance-containing gel is produced from theactive substance, a mixture of different permeation enhancers and agelatinizing agent, and is extruded between two layers of adhesive.Subsequently, individual, active substance-containing patches arepunched out from the thus produced active substance-containing laminate.

WO 00/37058 A1 discloses transparent nicotine TTSs exhibiting an opacityindex of 17.04% and 19.66%, respectively. They are produced inaccordance with the method described in U.S. Pat. No. 5,004,610.SCOTCHPAK® 1220 from the 3M Company, or SARANEX® from the Dow ChemicalCompany are used as transparent backing layers. Furthermore, a film madeof BARANES® may also be used as the transparent backing layer; BARANES®is a graft copolymer material of 73 to 77% acrylonitrile and about 27 to23% methacrylate, which is produced in the presence of 8 to 18 percentby weight of butadiene/acrylonitrile copolymers containing about 70percent by weight of butadiene-based polymer units.

To produce nicotine-containing TTSs, the pad printing method known fromEP O 303 025 A1 may be employed. In this process, amounts of 91 mg ofsolution are printed onto a pressure-sensitive adhesive surface ofacrylate using an oval silicone foam rubber pad of a Shore hardness of 6and a 50 percent by weight solution of nicotine in MIGLYOL® 812.

Finally, from DE 44 00 769 (whose United States equivalent is U.S. Pat.No. 6,187,322 incorporated herein by reference) a method for theproduction of sheet-like administration forms is known wherein aflowable preparation is transferred, with great accuracy, onto anonwoven-like substrate of defined area by a distributor plate of anapplication device. The distribution plate is provided with at least onepassage and the substrate is brought into contact with said distributorplate.

SUMMARY OF THE PRESENT INVENTION

It was the object of the present invention to provide a transdermaltherapeutic system and a method for the production thereof wherein thedrawbacks described hereinabove are avoided. More particularly, the aimis to provide a fiber-free TTS as well as a printing method for itsproduction.

This object has been achieved by a transdermal therapeutic system whichcan do without fibrous constituents.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In a preferred embodiment, the TTS according to the invention comprisesan active substance-impermeable, light-permeable backing layer, at leastone light-permeable pressure-sensitive adhesive layer, onto which anactive substance-containing preparation has been applied, and adetachable protective layer. The TTS is free of fibrous constituents.Any further, optionally present reservoir layers or matrix layers arealso free of fibers and permeable to light. Hence, this embodiment ofthe TTS according to the invention consists exclusively oflight-permeable layers and is free of fibrous constituents.

A light-permeable layer is understood to be a transparent or translucentlayer. A transparent layer allows light to pass through it almostunhindered, whereas a translucent layer allows most of the light to passthrough but scatters the light diffusely. The layers of a preferredembodiment of the inventive TTS are clear (totally) transparent.However, at least one of the layers of the inventive TTS may also betinted or—due to portions of organic and/or inorganic colorpigments—colored to such a degree that their transparency depends on thewavelength of the light. In this way, totally or partiallylight-impermeable TTSs can be provided.

In another preferred embodiment, the inventive TTS is skin-colored. TheTTS is thereby less conspicuous. As a rule, users indeed preferinconspicuous patches so that other people are less likely to notice andfind out about the user's need for treatment.

To produce skin-colored TTSs, the backing layer may be lacquered in askin color. Although it is not possible to provide the backing layerwith a uniform opaque skin color tone that will correspond to all skincolor tones present in the world population. But otherwise identicalactive substance patches can be provided with differently coloredbacking layers, each color being adapted to one of the skin color tonespresent in the world population so that the patch will be acceptable toa rather large number of users whose skin color differs only in nuance.

A fibrous constituent in the sense of the present invention isunderstood to mean relatively long, thin and flexible structures ofnatural or synthetic material. The fibrous constituents of naturalmaterials include, for example, plant fibers, animal fibers and mineralfibers. Plant fibers, such as bast, cotton, hemp, coconut, linen, kapokor ramie, generally consist of cellulose. The animal fibers include silkand hair (wool). A naturally occurring mineral fiber is asbestos. Thesynthetic fibers include fibers of perlon, nylon, but also syntheticsilk, glass fibers and carbon fibers. A number of fibers together formlarger structures. Thus, textile fibers may jointly form a thread, arope or a fabric. Cellulose fibers, for example, are used for themanufacture of paper and textiles. In the field of transdermaltherapeutic systems, fibers are mainly used in the form of nonwovens,paper, long-fiber paper and textile sheet material having a supportingand/or distributing function or having a reservoir function.

The pressure-sensitive adhesive layer and/or the optionally presentreservoir layer(s) or matrix layer(s) of the TTS according to theinvention may comprise a material which is selected from a groupconsisting of pressure-sensitive adhesive polymers based on acrylic acidand/or methacrylic acid as well as esters thereof, polyacrylates,isobutylene, polyvinyl acetate, ethylene-vinyl acetate, natural and/orsynthetic rubbers, for example acrylonitrile-butadiene rubber, butylrubber or neoprene rubber, styrene-diene copolymers such asstyrene-butadiene block copolymers, and hot-melt adhesives, or which isproduced on the basis of pressure-sensitive adhesive silicone polymersor polysiloxanes.

Preferably, the material comprising the pressure-sensitive adhesivelayer is selected from the group comprising cationic copolymers based ondimethylaminoethyl methacrylate and neutral methacrylic esters, forexample EUDRAGIT® E 100, and neutral copolymers based on butylmethacrylate and methyl methacrylates, for example PLASTOID® B.

For transparent or translucent TTSs, the pressure-sensitive adhesivelayer of the TTS must be permeable to light. The pressure-sensitiveadhesive layer is preferable clear-transparent, but can also be tintedor colored.

The backing layer, which is connected to the pressure-sensitive adhesivelayer or to a reservoir layer or matrix layer, which is optionallyprovided in addition thereto, is impermeable to the active substance tobe administered with the respective TTS and has occlusive properties.The backing layer of the TTS according to the invention may be permeableto light. It is free of fibrous constituents. In a particularlypreferred embodiment, the backing layer is colorless, that is, it isclear-transparent. However, the light-permeable backing layer may alsobe tinted, or it may be colored due to proportions of organic and/orinorganic color pigments contained therein, so as to be totally orpartially impermeable to light.

In other embodiments, the TTS according to the invention may be entirelyor partially impermeable to light. It is particularly preferred that theTTS be skin-colored, for example by providing a backing layer that islacquered in a skin color. For the backing layer, any materials may beused that meet the aforementioned requirements.

Such materials may, for example, be polymers from the group comprisingpolyethylene terephthalate, plasticized vinyl acetate-vinyl chloridecopolymers, nylon, ethylene-vinyl acetate copolymers, plasticizedpolyvinyl chloride, polyurethane, polyvinylidene chloride,polypropylene, polyethylene or polyamide.

The transdermal therapeutic system according to the invention containsat least one pharmaceutically active substance which can be delivered toa person via the skin. Suitable as the active substance are, inprinciple, any transdermally applicable pharmaceutical active substanceswhich can be contained, as single active substances or in combinationwith one another, in a TTS and which can be administered transdermally.At room temperature, the active substance may be a solid but may also beliquid. Both non-volatile active substances such as fentanyl, but alsovolatile active substances such as nicotine are suitable foradministration with the TTS according to the invention.

Further active substances, which may be contained in a TTS according tothe invention, are, for example, alprostadil, buprenorphine, clonidine,dexamethasone, dextroamphetamine, diclofenac, dihydrotestosterone,estradiol (also in combination with androgenic or progestinic activesubstances), fentanyl, flurbiprofen, lidocaine, methylphenidate,nitroglycerin, rotigotine, salicylic acid, scopolamine, testosterone andtulobuterol.

The TTS according to the invention is manufactured without use offibrous constituents, by applying the active substance by a suitableprinting method onto the fiber-free pressure-sensitive adhesive layer.

As a printing method, the pad printing method is particularly suitablefor loading the TTS with an active substance. In this process, aflowable active substance preparation is transferred onto thepressure-sensitive adhesive layer by using a pad. This printing methodis carried out at a constant temperature, thereby achieving high dosageaccuracy.

In a further suitable printing method, which, surprisingly, is suitablefor the production of the transdermal therapeutic systems according tothe present invention, the preparation containing the active substanceis transferred, by a distributor plate of an application device, ontothe fiber-free pressure-sensitive adhesive layer.

To manufacture the TTS according to the invention, initially afiber-free, preferably transparent, pressure-sensitive adhesive layer,located on an active substance-impermeable carrier layer, may beproduced. Individually dosed portions of a preparation containing activesubstance are applied to the pressure-sensitive adhesive layer byemploying a suitable printing method.

In a further step, the backing layer is applied to thepressure-sensitive adhesive layer, which is provided with the activesubstance-containing preparation, in such away that the activesubstance-containing preparation can no longer exit at that side of theresultant composite laminate. Finally, individual TTSs are produced fromthe thus-obtained intermediate product by cutting and/or punching. Theintermediate product, as the case may be, may comprise further reservoiror matrix layers and/or an active substance release-controlling membranewhich likewise is free of fibers and which, if required, is permeable tolight. In the finished TTS, the active substance-impermeable carrierlayer represents the detachable layer.

However, after applying the active substance-containing preparation, butbefore applying the backing layer, it is also possible to singularizeTTSs from the composite laminate, which has by then been formed and tosubsequently cover the TTSs with a backing layer.

Thus, the method for the production of a transdermal therapeutic systemis characterized in that:

an active substance-impermeable carrier layer or an optionally presentreservoir layer or matrix layer is provided with a fiber-freepressure-sensitive adhesive layer;

individually dosed portions of a flowable, active substance-containingpreparation are applied onto the pressure-sensitive adhesive layer by aprinting method; and

in a further step, an active substance-impermeable, fiber-free backinglayer is applied to the pressure-sensitive adhesive layer, which hasbeen provided with the active substance-containing preparation.

The TTSs are able to be singularized, by cutting and/or punching, priorto or following the application of the active substance-containingpreparation, from the composite laminate which has by then been formed.

To produce the TTS according to the present invention, the activesubstance must be present in a flowable state which permits singledosage by a suitable printing method. In the case of active substanceswhich under normal manufacturing conditions are present as solids, thisis done by adding suitable solvents as well as, as the case may be, byadding further auxiliary substances by which the viscosity of the activesubstance preparation can be adjusted. Suitable as solvents are, inprinciple, any of the conventional organic solvents, such as ethanol,isopropyl alcohol, heptane, hexane, ethyl acetate, petroleum ether,benzine, acetone, glycerol, DEET (N,N-diethyl-3-methylbenzamide), THF aswell as many oils, for example silicone oil, paraffin, triglycerides,neutral oil or plant oils.

Liquid active substances may be applied directly by the printing method.Usually, however, liquid active substances, too, are employed in theform of a liquid that exhibits the desired viscosity as a result of anaddition of suitable solvents and/or auxiliary substances.

The viscosity of the active substance-containing preparation to be usedas the printing medium is preferably in the range of 10 to 100 dPa·s,especially preferably in a range of 15 to 25 dPa·s at room temperature,e.g. about 20 to 25° C.

By performing the printing method at a temperature which is as constantas possible, it is possible to achieve a high accuracy of dosage. Theprinting method is preferably performed at room temperature, but canalso be carried out at lower or higher temperatures.

In a preferred manufacturing process, the active substance is mixed witha solution, suspension or dispersion of a polymer that is also aconstituent of the fiber-free pressure-sensitive adhesive layer of theTTS to be produced. In that case, the viscosity of the mixture can beadjusted by adjusting the ratio of active substance topressure-sensitive adhesive such that the mixture can be employed as aprinting medium. This mixture is then used as the printing medium.Preferred polymers for the production of the printing medium arecationic polymers based on dimethylaminoethyl methacrylate and neutralmethacrylic esters, such as EUDRAGIT® E 100, and neutral copolymersbased on butyl methacrylate and methyl methacrylates, for examplePLASTOID® B.

The method is especially well suited for active substances which at roomtemperature are liquid and/or highly volatile so that dissolving theactive substance in the adhesive and drying at temperatures between 60and 100° C. is not possible because the active substance is too highlyvolatile or too thermosensitive. These active substances include, forexample, nicotine, nitroglycerin, bupropion, but also essential oilssuch as menthol, camphor, turpentine, or oils from mountain pine,peppermint, spearmint, lemon or cloves, as well as almost all of thepolypeptides and proteins. DEET and DMSO also belong to the highlyvolatile substances.

In a particularly preferred method, EUDRAGIT® E 100 is dissolved innicotine, and this active substance solution is used as the printingmedium. The quantity ratio of nicotine to EUDRAGIT® is preferably 1:1 to1:3, especially preferably 1.4:1 up to 2.4:1.

Other active substances that are suitable for being applied with thismethod are alprostadil, buprenorphine, clonidine, dexamethasone,dextroamphetamine, diclofenac, dihydrotestosterone, estradiol (also incombination with androgenic or progestinic active substances), fentanyl,flurbiprofen, lidocaine, methyl phenidate, nitroglycerin, rotigotin,salicylic acid, scopolamine, testosterone and tulobuterol.

EXAMPLE

A pressure-sensitive adhesive mass, consisting of 2.0825 kg of a 40%solution of a self-crosslinking acrylate polymer (of 2-ethylhexylacrylate, vinyl acetate, acrylic acid and titanium chelate ester;commercially available under the designation DUROTAK® 280-2416 (NationalStarch & Chemical B. V.)) in a mixture of acetic acid ethyl ester,ethanol, hexane and menthol, 147 g of an acrylic resin ofdimethylaminoethyl methacrylate and neutral methacrylic esters(EUDRAGIT® E 100 from the Rohm-Pharma company), as well as 20 g of amixed-acidic triglyceride of fractionated coconut fatty acids C₈-C₁₀(MIGLYOL® 812 from the Dynamit Nobel company) was applied onto aprotective layer which had been vapor- coated on one side and renderedadhesive on both sides. Subsequently, the solvent was evaporated at 50to 80° C. A pressure-sensitive adhesive layer having a weight per unitarea of approximately 300 g/m² was obtained. From the thus-producedpressure-sensitive adhesive layer, circular blanks of a diameter of 65mm were punched, and the projecting margins were removed.

A dose of 102 mg nicotine was applied onto the pressure-sensitiveadhesive layer of each circular blank as active substance preparation inthe form of a solution (140 g of nicotine in 100 g EUDRAGIT° E 100). Tothis end, a pad printer, with a steel printing plate, having a rounddepression of 39 mm and an etching depth of 240 μm as the printingstyle, was used for printing the blanks. As pad, an oval silicone foamrubber pad, with a Shore hardness of 6, was used. The nicotine—EUDRAGIT®solution was used as the printing medium, and circular layers of saidprinting medium were placed on the blanks by using the pad.

A transparent, 15-μm-thick polyester film was immediately laminated, asa nicotine-impermeable backing layer, onto the “patches” produced in theabove-described manner. Subsequently, the finished products were sealedin four-side-sealed bags made of a known composite packaging material(BAREX®).

What has been described above are preferred aspects of the presentinvention. It is of course not possible to describe every conceivablecombination of components or methodologies for purposes of describingthe present invention, but one of ordinary skill in the art willrecognize that many further combinations and permutations of the presentinvention are possible. Accordingly, the present invention is intendedto embrace all such alterations, combinations, modifications, andvariations that fall within the spirit and scope of the appended claims.

That which is claimed:
 1. A method for producing a transparenttransdermal therapeutic system comprising the steps of: providing alight-permeable, fiber-free pressure-sensitive adhesive layer; printingindividually dosed portions of a flowable, active substance-containingpreparation onto the light-permeable, fiber-free pressure-sensitiveadhesive layer, said flowable active substance-containing preparationcomprising a polymer which is also a constituent of the light-permeable,fiber-free pressure-sensitive adhesive layer to form a compositelaminate; and applying an active substance-impermeable, light-permeable,fiber-free backing layer onto the composite laminate of the printingstep, forming singularised transparent transdermal therapeutic systemsby at least one of cutting and punching following said step of applyingthe active substance-impermeable, light-permeable, fiber-free backinglayer, and said printing method is a method comprising the step oftransferring the active substance-containing preparation onto thelight-permeable, fiber-free pressure-sensitive adhesive layer by adistributor plate of an application device, said distributor plate beingprovided with at least one passage.
 2. The method according to claim 1,wherein said printing method is a pad printing method.
 3. The methodaccording to claim 1, wherein said polymer is selected from the groupconsisting of cationic copolymers based on dimethylaminoethylmethacrylate and neutral methacrylic esters, and neutral copolymersbased on butyl methacrylate and methyl methacrylates.
 4. The methodaccording to claim 1, comprising the step of adding auxiliary substancesto adjust the viscosity of the flowable, active substance-containingpreparation.
 5. The method according to claim 1, wherein saidlight-permeable, fiber-free backing layer is selected from the groupconsisting of completely or partially light-permeable backing layers,and skin-colored backing layers.
 6. The method according to claim 5,wherein said light-permeable, fiber-free backing layer is lacqueredskin-colored.
 7. The method according to claim 1, wherein saidlight-permeable, fiber-free backing layer comprises a material selectedfrom the group consisting of polyethylene terephthalate, plasticizedvinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetatecopolymers, plasticized polyvinyl chloride, polyurethane, polyvinylidenechloride, polypropylene, polyethylene and polyamide.
 8. The methodaccording to claim 1, wherein said light-permeable, fiber-freepressure-sensitive adhesive layer comprises a material which is selectedfrom the group consisting of pressure-sensitive adhesive polymers basedon at least one of acrylic acid and methacrylic acid, esters of at leastone of acrylic acid and methacrylic acid, polyacrylates, isobutylene,polyvinyl acetate, ethylene-vinyl acetate, at least one of natural andsynthetic rubbers, styrene-diene copolymers, and hot-melt adhesives, orwhich is produced on the basis of pressure-sensitive adhesive siliconepolymers or polysiloxanes.
 9. The method according to claim 8, whereinsaid material is selected from the group consisting of cationiccopolymers based on dimethylaminoethyl methacrylate and neutralmethacrylic esters, and neutral copolymers based on butyl methacrylateand methyl methacrylates.
 10. The method according to claim 1, whereinsaid active substance is a liquid or solid at room temperature.
 11. Themethod according to claim 1, wherein said active substance is selectedfrom the group consisting of alprostadil, buprenorphine, bupropion,clonidine, dexamethasone, dextroamphetamine, diclofenac,dihydrotestosterone, estradiol, estradiol in combination with androgenicor progestinic active substances, fentanyl, flurbiprofen, lidocaine,methylphenidate, nicotine, nitroglycerin, rotigotine, salicylic acid,scopolamine, testosterone, tulobuterol and essential oils.
 12. Themethod according to claim 1, wherein the flowable activesubstance-containing preparation comprises a cationic polymer which isalso a constituent of said pressure-sensitive adhesive layer.
 13. Themethod according to claim 1, wherein the application of the activesubstance-containing preparation gives rise to an active substanceloading gradient within the inventive pressure-sensitive adhesive layer.14. The method according to claim 1, wherein said active substance is aliquid at room temperature, the pressure-sensitive adhesive is acationic copolymer comprising dimethylaminoethyl methacrylate andneutral methacrylic esters, and said pressure-sensitive adhesive alsocomprises self-crosslinking acrylate adhesive in addition to saidpressure-sensitive adhesive polymer.
 15. The method according to claim14, wherein said self-crosslinking acrylate adhesive and saidpressure-sensitive polymer are present at about a 5.7:1 ratio.
 16. Themethod according to claim 1, wherein said pressure-sensitive adhesivealone comprises mixed-acidic triglyceride of fractionated coconut fattyacids C8-C10.
 17. The method according to claim 1, wherein the activesubstance-containing preparation has a viscosity ranging from 10 to 100dPa·s.
 18. The method according to claim 17, wherein the activesubstance-containing preparation has a viscosity ranging from 15 to 25dPa·s.
 19. The method according to claim 1, said process furthercomprising evaporating solvent from said light-permeable, fiber-freepressure-sensitive adhesive layer prior to applying said activesubstance-containing preparation; and applying said activesubstance-impermeable, light-permeable, fiber-free backing layer ontothe light-permeable, fiber-free pressure-sensitive adhesive layerimmediately after applying said active substance-containing preparationonto the light-permeable, fiber-free pressure-sensitive adhesive layer.